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1.4 -- 29th July 1997



Cell Immunol 1997 Jun 15;178(2):117-123

Early steps in T cell development are affected by aging.

Thoman ML

Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.

Involution of the thymus accompanies aging, a process in which the organ diminishes in size and cellularity and becomes disorganized. The rate of T cell emigration from the thymus is markedly reduced with age, and phenotypic analyses have identified alterations in the relative proportions of the major thymocyte subpopulations. The present studies made use of the capacity of the thymus to regenerate following irradiation from an intrathymic radio-resistant precursor population. By analysis of the differentiation of this "wave" of thymocytes, it was determined that aging most severely affects the earliest developmental transitions. While the overall rate of differentiation does not appear to be affected in older mice, fewer thymic progenitors initiate differentiation. The reduced expansion of late pre-T cells in the middle-aged is due to the smaller pool size of these cells.

Mech Ageing Dev 1997 Jun;96(1-3):1-13

Genetic control of immune responsiveness, aging and tumor incidence.

Doria G, Biozzi G, Mouton D, Covelli V

Laboratory of Immunology, AMB-PRO-TOSS, Rome, Italy.

Age-related alterations of the immune system affect both antibody and cell-mediated immune responses, T-cell responses being more severely affected than B-cell responses. Within the T-cell population, aging leads to replacement of virgin by memory cells and to accumulation of cells with signal transduction defects. Changes in T-cell subsets and in cytokine production profiles may produce suitable conditions for T-cell-mediated disregulation of antibody responses characterized by the production of low affinity and self-reactive antibodies. Also B-cells exhibit intrinsic defects and natural killer (NK) cell activity a profound loss in old mice. Whether age-related immune disfunctions influence life span and tumor incidence has been examined in mice genetically selected for high or low antibody responsiveness. It has been found that genetic selection of vigorous antibody responses in most cases produces mice with longer life span and lower lymphoma incidence. Moreover, the results of genetic segregation experiments indicate that antibody responsiveness and life span are polygenic traits regulated by a small number of the same or closely linked loci. Mice genetically selected for high or low mitotic responsiveness to PHA exhibit low or high tumor incidence, respectively, but no difference in life span, suggesting that T-cell activity is restricted to immune surveillance of neoplastic transformation. Studies on mice genetically selected for resistance or sensitivity to chemical carcinogenesis have uncovered loci that control both resistance to tumor induction and longevity while have no effects on immunity and disease incidence. Thus, the relative role of the immune system in conditioning the duration and the biological quality of life remains to be determined.

Mech Ageing Dev 1997 Mar;94(1-3):55-69

The age-associated decline in immune function of healthy individuals is not related to changes in plasma concentrations of beta-carotene, retinol, alpha-tocopherol or zinc.

Gardner EM, Bernstein ED, Dorfman M, Abrutyn E, Murasko DM

Department of Medicine, Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.

The decline in the lymphoproliferative response to mitogenic stimuli shows marked heterogeneity in elderly individuals. Adequate nutriture is required for optimal immune function, yet nutritional status may be compromised in the elderly. To address whether this variation in the proliferative response of elderly individuals is related to their nutritional status, we studied 61 elderly (80.5 +/- 5.7 year-old) and 27 young (27.3 +/- 3.8 year-old) individuals participating in an ongoing assessment of their immune response to influenza vaccine. Ambulatory elderly individuals were recruited from five different retirement communities and were in good health upon enrollment in the study. Thirty-three percent of young and 54% of elderly subjects reported consuming micronutrient supplements daily during the study. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from fasting individuals twice, 4-6 weeks apart. At both times, proliferative responses to the mitogens phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) were significantly lower (P < 0.004) in the elderly compared to the young. However, at both times, elderly participants had plasma concentrations of beta-carotene, retinol, alpha-tocopherol and zinc that were either significantly greater than, or equal to, those of young subjects. No significant correlations between plasma concentrations of beta-carotene, retinol, alpha-tocopherol and zinc and level of proliferative responses to each stimuli were observed in elderly individuals at either time. Thus, the heterogeneity in the proliferative response to mitogenic stimuli exhibited by a healthy elderly population cannot be attributed to differences in these nutritional parameters.

Mech Ageing Dev 1997 Mar;94(1-3):71-83

Diminished activation of the MAP kinase pathway in CD3-stimulated T lymphocytes from old mice.

Gorgas G, Butch ER, Guan KL, Miller RA

Department of Pathology, University of Michigan, School of Medicine, Ann Arbor 48109, USA.

Stimulation of the ERK family of protein kinases ('extracellular signal regulated kinases', also known as MAP kinases) plays an important role in the activation of many cell types, including T lymphocytes. ERKs are activated when they are phosphorylated by an upstream activator, the dual-specific protein kinase MEK. To see if aging leads to an impairment of MEK activation in mouse T cells, we used a mobility shift assay in which activation of MEK leads to phosphorylation and altered mobility of ERK-2 kinase. Similarly, we monitored mobility of pp90rsk, a known ERK substrate, as an indication of ERK function. We found an age-related decline in the ability of mouse T cells to activate both MEK and ERK function in response to stimulation by antibodies to the CD3 chain of the T cell receptor. Aging did not alter the kinetics of enzyme activation, but did diminish (by about 2-fold) the maximal level of substrate converted into the slower migrating form. Naive and memory CD4 T cells from young mice were equally able to convert ERK2 to its slower migrating form, suggesting that the decline in MEK function is not likely to be attributable to the shift, with age, from naive to memory T cell predominance. Our data suggest that age-dependent declines in gene activation, including genes for key cytokines like IL-2, may be due to declines in the upstream signals that lead to activation of the MEK/ERK protein kinase cascade.

Brain Res 1997 Feb 28;749(2):283-289

Somatostatin and brain-derived neurotrophic factor mRNA expression in the primate brain: decreased levels of mRNAs during aging.

Hayashi M, Yamashita A, Shimizu K

Department of Cellular and Molecular biology, Primate Research Institute, Kyoto University, Inuyama, Aichi, Japan.

The expression of the genes for somatostatin (SRIF) and brain-derived neurotrophic factor (BDNF) was investigated in the central nervous system (CNS) of the macaque monkey (Macaca fuscata fuscata). Using Northern blot analysis, one SRIF mRNA transcript, 0.65 kb, and two BDNF mRNA transcripts, 1.6 and 4.0 kb in length, were detected in the monkey brain tissues. During the aging process (2 years, 10 years, and > 30 years), the ratio of SRIF mRNA/glyceraldehyde-3 phosphate dehydrogenase (G3PDH) mRNA significantly decreased (60-70%) in the hippocampus and in several cerebral subdivisions such as frontal cortex, temporal cortex, motor cortex, somatosensory cortex and visual cortex. BDNF mRNA was expressed in the various cerebral subdivisions and in the hippocampus. During the aging process, the gene expression of BDNF declined (20-50% for the 4.0 kb transcript, and 40-70% for the 1.6 kb transcript) in the various cerebral subdivisions. In the hippocampus, the level of the 1.6 kb mRNA at > 30 years old declined to 60% of the level at 2 years old, while the 4.0 kb mRNA did not change significantly during the aging process. Recent studies have shown that BDNF enhances the expression of SRIF mRNA in the rodent cerebral cortex (Nawa, H. et al., J. Neurochem., 60 (1993) 772-775; Nawa, H. et al., J. Neurosci., 14 (1994) 3751-3765). These studies and our present results suggest that the decrease in gene expression for a neurotrophic molecule, such as BDNF, might cause the levels of SRIF mRNA to decline in the primate brain during the aging process.

Brain Res 1997 Feb 28;749(2):329-334

Expression of activating transcription factor-2 (ATF-2), one of the cyclic AMP response element (CRE) binding proteins, in Alzheimer disease and non-neurological brain tissues.

Yamada T, Yoshiyama Y, Kawaguchi N

Department of Neurology, Chiba University, Chuo-ku, Japan.

Cyclic AMP response element (CRE) is a specific DNA sequence which mediates transcriptional activation in the response to the cyclic AMP-activated and protein kinase A dependent signaling pathway. We examined the localization of one of the CRE binding proteins which is preferentially expressed in the brain, activating transcription factor-2 (ATF-2), by immunohistochemistry and Southwestern histochemistry, using the brains of neurologically normal and Alzheimer disease (AD) cases. In all brains, the anti-ATF-2 antibody stained white matter microglial cells. In AD, the cytoplasm of some cortical neurons was also positively stained, but no such staining was seen in the neocortex in non-neurological cases staining. However, both the nuclei and cytoplasm of some hippocampal neurons were positive in non-neurological brain tissues. In AD, except for severely damaged areas such as CA1, positive neuronal staining was seen. Southwestern histochemistry gave the same results as immunohistochemistry. These data suggest that the localization of ATF-2 in cortical neurons in AD may reflect early pathological changes characteristic of AD, and that these histochemistrical methods may allow one to differentiate between healthy and mildly damaged neurons.

J Gerontol B Psychol Sci Soc Sci 1997 Jan;52(1):P28-P39

Patterns of motor impairement in normal aging, mild cognitive decline, and early Alzheimer's disease.

Kluger A, Gianutsos JG, Golomb J, Ferris SH, George AE, Franssen E, Reisberg B

Department of Psychiatry, New York University Medical Center, USA.

In order to determine the relationship between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 cases exhibiting mild cognitive impairment (MI), and 25 patients with mild Alzheimer's disease (AD) were examined using a broad array to motor/psychomotor and cognitive tests. Relative to the NL group, MI individuals (at risk for future decline to AD) performed worse on tasks involving fine and complex motor function (e.g., tracking and manual dexterity). AD patients also exhibited motor dysfunction on tasks assessing relatively more rudimentary motor control. Motor tasks were able to distinguish NL vs MI and NL vs mild AD individuals as effectively as cognitive tests of memory and language. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments may be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology.

Neurobiol Aging 1997 Jan;18(1):1-11

Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease.

De Leon MJ, George AE, Golomb J, Tarshish C, Convit A, Kluger A, De Santi S, McRae T, Ferris SH, Reisberg B, Ince C, Rusinek H, Bobinski M, Quinn B, Miller DC, Wisniewski HM

Department of Psychiatry, New York University School of Medicine, NY 10016, USA.

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD.

Brain Res Dev Brain Res 1997 Jan 2;98(1):1-8

Purkinje cell loss in heterozygous staggerer mutant mice during aging.

Hadj-Sahraoui N, Frederic F, Zanjani H, Herrup K, Delhaye-Bouchaud N, Mariani J

Laboratoire de Neurobiologie du Developpement, Institut des Neurosciences (CNRS URA 1488), Universite Pierre et Marie Curie, Paris, France.

The cerebellum on the heterozygous (+/sg) staggerer mutant mouse has recently been proposed as a model system in which to study the genetic contribution to the normal process of central nervous system aging since there is significant loss of neurons from 3 to 12 months of age (Shojaeian-Zanjani, H., Mariani, J., Delhaye-Bouchaud, N., and Herrup, K. (1992) Dev. Brain Res., 67, 153-160). In the current study we extend our analysis of the changes in Purkinje cell numbers up to 24 months of age in +/sg and C57BL/6J wild-type mice. At 13 and 18 months, while wild-type Purkinje cell numbers remain unchanged, there is a 22-26% loss in the number of Purkinje cells in +/sg after which no further cell loss is observed. Between 18 and 24 months, however, a 22% loss of Purkinje cell occurs in +/+ animals, with the result that by 2 years of age, the size of the Purkinje cell population is again similar in both genotypes. Analysis of the cell loss in both the mediolateral and the anteroposterior dimensions, as well as the immunostaining of Purkinje cells in frontal sections, reveal no obvious regional variation in the Purkinje cell loss. These results suggest that in +/sg, a precocious process of aging affects the size of the Purkinje cell population.



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